There is an urgent need to develop effective and implementable strategies to prevent HIV infection. Given the lack of a vaccine, and that half of all infections occur in women, development of an HIV-inhibiting microbicide is a growing priority. Consensus exists that an effective microbicide may be feasible. Simian AIDS models have helped guide the development and prioritization of HIV prevention strategies. However, current models may not provide realistic pre-clinical tests of HIV prevention efficacy. The viral inoculum sizes used to infect macaques exceed those that humans are exposed to, and may lead to underestimation of the efficacy of HIV preventions. The small inocula associated with most human HIV transmission events, combined with the likely stochastic nature of early infection events, may even make HIV transmission particularly susceptible to intervention. This proposal brings together investigators with expertise in the mathematical analysis of HIV transmission events, simian AIDS model development, and AIDS virology and immunology, to develop a challenge model that better recapitulates HIV transmission. The model uses intravaginal inoculation with low doses of a CCR5-utilizing SHIV. Overall hypotheses: 1) Low-dose inocula, applied repeatedly, will achieve experimental SHIV infection with enough reproducibility so that prevention efficacy studies could be performed; power analyses predict that the animal numbers required to demonstrate efficacy are similar to those used in current high-dose challenge models, and 2) A low-dose challenge model will provide a more sensitive, physiologically relevant measure of the efficacy of microbicides, vaccines or other preventions. Efficacy would be demonstrated by showing that an intervention increases the number of challenges required to achieve infection, compared to controls. Specific aims: 1) Define the animal infectious dose 50% (ID50) for SHIV-SF162P inoculation of pig-tailed macaques, and 2) Determine whether repeated challenges with the ID50 result in reproducible infection. If validated, this low dose model could help define relevant correlates of protection, and would be ideal for testing the efficacy of HIV microbicides, vaccines, and pre-exposure prophylaxis strategies. Efficacy measures obtained in the low dose model could be compared to those obtained in 'high virus challenge' models, to see if the low-dose model detects efficacy that is masked by high virus inocula.